Viewpoints

STEPping into Position: A New Player in the NMDA Receptor Game

The posttranslational modification of proteins—phosphorylation or dephosphorylation of serine and threonine residues—is usually
considered essential for the initiation and maintenance of long-term potentiation (LTP) and long-term depression (LTD) in
neural plasticity. Pelkey et al. have identified at the N-methyl-d-aspartate (NMDA) receptor a protein tyrosine phosphatase—a member of the striatal-enriched phosphatase family, termed STEP61—that appears to antagonize the effects of Src-mediated tyrosine phosphorylation during the facilitation of LTP. Mansuy reviews
the findings of STEP61 as a participant in modulating NMDA receptor-associated plasticity and discusses how differing populations of serine, threonine,
and tyrosine phosphorylated or dephosphorylated residues might finely tune plasticity.

Cunningham and colleagues have reported that the unfolded protein response (UPR) stimulates cellular influx of calcium, thereby
activating calcium-dependent proteins such as calcineurin and calmodulin, and that this activation may be important for UPR.
However, the authors have more importantly identified that the calcium signal is part of a larger pathway, termed the calcium
cell survival (CCS) pathway, which is activated in response to several different types of stress. A key point is that the
activation of the calcium-mediated events might lead to drug resistance in pathogenic fungi. Cronin examines these findings
and discusses how the CCS might be subverted to render resistant fungi sensitive to treatment.

Erik Sahai

p53 Moves Into Control of Cell Morphology

Altered regulation of cell cycle, DNA repair, and apoptosis may not be the only ways that loss of p53 contributes to tumorigenesis.
Roux and colleagues describe how the tumor suppressor protein p53 can regulate Cdc42-dependent (but neither RhoA- nor Rac-dependent)
effects on cell morphology. The activation of p53 tends to inhibit the formation of Cdc42-dependent filopodia, pointing to
a new way in which p53 exerts its tumor-suppressing activity: the prevention of cell spreading and motility. Sahai reviews
these observations and discusses how insights gained from these studies will most likely lead to the identification of new
targets for cancer therapy.

Tooraj Mirshahi and

Diomedes E. Logothetis

GIRK Channel Trafficking: Different Paths for Different Family Members

Ma et al. have reported that different G protein-regulated inwardly rectifying K+ (GIRK) channels composed of combinations of Kir3.1-Kir3.2-Kir3.3-Kir3.4 are localized to different subcellular compartments.
Kir3.3 seems to target Kir3.1-containing channels to lysosomes, whereas Kir3.1-containing channels also consisting of Kir3.2
or Kir3.4 are successfully expressed at the cell surface. The new results suggest a mechanism whereby the surface expression
of heterotetramers is controlled and thus channel density can be properly maintained. Mirshahi and Logothetis discuss the
results and their implications for channel trafficking, but caution that we are far from understanding the whole regulatory
process and that, indeed, other mechanisms participate in maintaining channel density.

Reviews

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Jason M. Haugh

Localization of Receptor-Mediated Signal Transduction Pathways: The Inside Story

The old conventional wisdom stated that internalized growth factor receptors were incapable of transmitting signals; however,
new research indicates that internalized receptors can still send signals, but that the quality and quantity of those signals
are likely to differ from those of their plasma-membrane-bound brethren. The maintenance of active pathways in concert with
the deactivation of others all ows for fine-tuning cellular responses to external stimuli. These findings have implications
for cell motility, metabolism, and cell cycling.

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P. Michael Conn,

Alfredo Leaños-Miranda,

and Jo Ann Janovick

Protein Origami: Therapeutic Rescue of Misfolded Gene Products

Not only must proteins be synthesized, folded, and modified—processes that may all be related—but they must also be trafficked
to appropriate subcellular destinations. Thus, the regulation of trafficking of any given protein may represent a means for
the regulation of its function. The development of therapeutics that affect protein localization—either by nudging the reluctant
protein on to a desired location or by stranding the overeager protein mid route—could become a specific way of targeting
certain disease states.

The cyclic nucleotides cAMP and cGMP bind to and regulate a vast variety of proteins including phosphodiesterases (PDEs),
which act to terminate signaling. PDEs are thus important drug targets, a fact underscored by the success of Viagra®. A key
to the design of new PDE-targeting drugs may lie in an age-old trick—about two billion years old, to be precise. Specific
protein motifs—the GAF domains—have evolved in mammals as well as cyanobacteria, and bind cyclic nucleotides to regulate a
broad array of proteins. A newly described crystallographic structure gives us the first glimpse into the binding of a cyclic
nucleotide to a GAF motif from a PDE, and provides important insights regarding the regulatory binding (as opposed to substrate
binding) of cGMP.